Premature birth poses a substantial risk for long-term developmental and cognitive impairment, even in the absence of overt brain injury. We hypothesize that the neonatal brain is unusually sensitive to sub- lethal hypoxic and ischemic injury because of the level of synaptic remodeling and apoptotic pruning that occurs during this period. However, the factors that underlie synaptic plasticity or that mediate the apoptotic response are poorly understood and almost impossible to study in neonatal children. Based on a new substantial body of evidence it has become clear that the neuronal spectrin cytoskeleton contributes to synaptic organization, shape, and responsiveness, and may also play a role in mediating the cells response to apoptosis inducing signals. Closely associated with this role appears to be its sensitivity to Ca++ activated neutral proteases lie u-calpain and to the interleukin converting protease (ICE) family member CPP32. In order to study the in vivo role of calpain and CPP32 cleavage of spectrin on processes involved with brain development, and its response to injury, transgenic mice will be prepared that express brain spectrin that has been mutated so as to reduce its susceptibility to calpain and /or CPP32 cleavage. these mice will be analyzed for evidence of impaired brain maturation, electrophysiologic function, synaptic density, apoptotic arrest, and other changes. The response of these mice to sub lethal hypoxic and ischemic stress will also be evaluated. Collectively, these studies promise to yield our first real insights into the role of the spectrin skeleton in synapse ecology and neuronal apoptosis, and may provide a unique in vivo model for examining the consequences of perinatal brain damage.